The physiological role of the renin-angiotensin system is to regulate blood pressure and to maintain sodium and volume homeostasis. The key events in this system are the conversion of the polypeptide angiotensinogen to the decapeptide angiotensin I (AI) and the subsequent cleavage of the latter to give the octapeptide angiotensin II (AII). The latter peptide is a potent vasoconstrictor and a potentiator of aldosterone release. Due to potent pressor effects, AII plays a significant role in hypertension and as such has been the target for the development of antihypertensive agents.
One approach to finding such agents is to search for potent inhibitors of the angiotensin converting enzyme. Inter alia, the latter enzyme catalyzes the conversion of AI to AII. This approach has met with success and a number of such agents are used therapeutically to treat hypertension. Another approach is to find specific inhibitors of renin, an aspartyl protease which cleaves angiotensinogen to AI. Since angiotensinogen is the only known natural substrate for renin, this approach has the desirable feature of being aimed at a potential antihypertensive agent with a single mode of action.
In the pursuit of this goal, a great deal of attention has been given to designing renin inhibitors which mimic the natural substrate angiotensinogen. Much of this effort has been focused on the design of analogous substrates incorporating therein a non-cleavable mimic (i.e. a transition state analog) of the renin cleavage site (i.e. Leu-Val) of human angiotensinogen. As a result, a number of potent renin inhibitors have been identified in the laboratory and the ability of renin inhibitors to lower blood pressure and to reduce plasma renin activity has now been demonstrated in the clinic. For a recent review on renin inhibitors, see W. J. Greenlee, Medical Research Reviews, 10, 173 (1990). Nevertheless, progress toward obtaining the ideal renin inhibitor continues to be plagued with problems of low oral absorption, limited bioavailability and rapid elimination, mainly due to the peptidic nature of the inhibitors presently under investigation. Hence, there is a need for a readily administered, effective renin inhibitor.
The renin inhibitors of the present application belong to the class of transition state analog inhibitors of renin. They are characterized by having a N-(2-oxygenated-ethyl)succinamoyl moiety incorporated into their structure. This feature, in combination with their non-peptidic character and their relatively lower molecular weight, apparently contribute beneficially to the stability, absorption and bioavailability of the inhibitors. Another feature of the present inhibitors is their relative specificity for renin as compared to other aspartyl proteases.
The following references exemplify past efforts that have been made in the search for renin inhibitors with improved characteristics:
W. J. Greenlee et al., European patent application 278 158, published Aug. 17, 1988; PA1 A. A. Patchett et al., U.S. Pat. No. 4,839,357, issued Jun. 13, 1989; PA1 D. J. Kempf et al., European patent application 402 646, published Dec. 19, 1990; PA1 P. D. Williams et al., U.S. Pat. No. 5,001,113, issued Mar. 19, 1991; PA1 H. Heitsch et al., Canadian patent application 2,025,093, published Mar. 13, 1991; PA1 W. J. Greenlee et al., U.S. Pat. No. 5,006,511, issued Apr. 9, 1991; PA1 P. D. Williams, Canadian patent application 2,034,524, published Jul. 20, 1991; PA1 H. N. Weller and D. E. Ryono, U.S. Pat. No. 5,055,466, issued Oct. 8, 1991; and PA1 S. H. Rosenberg et al., U.S. Pat. No. 5,063,208, issued Nov. 5, 1991. PA1 (a) HO--CH(R.sup.3)CH.sub.2 wherein R.sup.3 is hydrogen, lower alkyl, lower cycloalkyl, phenyl, benzyl, or an unsubstituted, monosubstituted or disubstituted five- or six-membered heterocyclic ring (hereinafter designated as "Het") containing one or two heteroatoms selected from the group of N, O or S, wherein each substituent is selected independently from the group consisting of lower alkyl, lower alkoxy, halo, hydroxy, amino and lower alkylamino; PA1 (b) HO--CH.sub.2 CH(R.sup.4) wherein R.sup.4 is lower alkyl, (lower cycloalkyl)-(lower alkyl), phenyl(lower)alkyl or .alpha.-hydroxyphenylmethyl; PA1 (c) HO--CR.sup.5 (R.sup.6)CH.sub.2 wherein each of R.sup.5 and R.sup.6 is lower alkyl; or R.sup.5 and R.sup.6 together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl), 1,1-(4-hydroxycyclohexanediyl) or 1,1-(4-oxocyclohexanediyl); PA1 (d) (lower alkoxy)CR.sup.5A (R.sup.6A)CH.sub.2 wherein each of R.sup.5A and R.sup.6A is lower alkyl; or R.sup.5A and R.sup.6A together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl); and PA1 (e) (lower alkyl)C(O)CH.sub.2 ; PA1 (a) R.sup.7 is hydrogen or lower alkyl and R.sup.8 is hydrogen, lower alkyl or lower alkyl monosubstituted with lower cycloalkyl, phenyl or Het wherein Het is as defined hereinbefore; or PA1 (b) R.sup.7 is lower alkyl and R.sup.8 is R.sup.9 R.sup.10 N--Alk.sup.2 wherein R.sup.9 and R.sup.10 each independently is hydrogen or lower alkyl and Alk.sup.2 is a divalent alkyl radical derived by the removal of two hydrogen atoms, each from a different carbon atom, of a straight or branched chain hydrocarbon containing from two to six carbon atoms; or PA1 (c) R.sup.7 is lower alkyl and R.sup.8 is QC(O)(CH.sub.2).sub.m wherein Q is piperidino, morpholino, thiomorpholino, piperazino or 4-(lower alkyl)-1-piperazinyl and m is the integer 1 or 2; or PA1 (d) R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, thiomorpholino or 4-(lower alkyl)-1-piperazinyl; PA1 R.sup.2 is lower alkyl, (lower cycloalkyl)methyl or Het--CH.sub.2 wherein Het is as defined hereinabove; and PA1 B is a transition state analog of the formula NHCH(R.sup.11)CH(OH)--Z wherein R.sup.11 is lower alkyl, (lower cycloalkyl)methyl, benzyl, [4-(lower alkyl)phenyl]methyl, [4-(lower alkoxy)phenyl]methyl, or (4-halophenyl)methyl, and Z is lower alkyl, lower cycloalkyl, (lower cycloalkyl)methyl, C(O)OR.sup.12 wherein R.sup.12 is lower alkyl, the radical of formula 2 ##STR1## wherein R.sup.13 is lower alkyl and R.sup.14 and R.sup.15 each is hydrogen or lower alkyl, [(1-methyl-1H-tetrazol-5-yl)thio]methyl or CH(OH)R.sup.16 wherein R.sup.16 is lower alkyl or lower cycloalkyl, with the provisos (1) that the asymmetric carbon atom bearing R.sup.11 has the (S) configuration, (2) that when Z is lower alkyl, lower cycloalkyl, (lower cycloalkyl)methyl or the radical of formula 2 as defined hereinabove then the asymmetric carbon atom bearing the hydroxyl in the NHCH(R.sup.11)CH(OH) radical has the (S) configuration, (3) that when Z is C(O)OR.sup.12 wherein R.sup.12 is lower alkyl, or when Z is [(1-methyl-1H-tetrazol-5-yl)thio]methyl, then the asymmetric carbon atom bearing the hydroxyl in the NHCH(R.sup.11)CH(OH) radical has the (R) configuration, (4) that when Z is CH(OH)R.sup.16 wherein R.sup.16 is lower alkyl or lower cycloalkyl the asymmetric carbon atoms bearing the hydroxyls in the NHCH(R.sup.11)CH(OH) and Z radicals have respectively the (R) and (S) configuration, and (5) that the carbon atom bearing R.sup.2 has the (R) configuration, except when R.sup.2 is CH.sub.2 --Het wherein Het has a nitrogen atom at the point of attachment, and/or has a sulfur atom next to the atom at the point of attachment, of the Het to the methylene (CH.sub.2), then in the instance of this exception the carbon atom bearing R.sup.2 has the (S) configuration; or a therapeutically acceptable acid addition salt thereof. PA1 (a) HO--CH(R.sup.3)CH.sub.2 wherein R.sup.3 is hydrogen, lower alkyl, cyclohexyl, phenyl, benzyl or Het wherein Het is as defined hereinabove, PA1 (b) HO--CH.sub.2 CH(R.sup.4) wherein R.sup.4 is cyclohexylmethyl, benzyl or .alpha.-hydroxyphenylmethyl, PA1 (c) HO--CR.sup.5 (R.sup.6)CH.sub.2 wherein R.sup.5 and R.sup.6 each is lower alkyl, or together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl), 1,1-(4-hydroxycyclohexanediyl) or a 1,1-(4-oxocyclohexanediyl); PA1 (d) (lower alkoxy)CR.sup.5A (R.sup.6A)CH.sub.2 wherein each of R.sup.5A and R.sup.6A is lower alkyl; or R.sup.5A and R.sup.6A together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl); and PA1 (e) (lower alkyl)C(O)CH.sub.2 ; PA1 R.sup.1 is hydrogen; the oxygen-bearing radical (a), (b) or (c) as defined hereinabove; HO--Alk.sup.1 --CH.sub.2 CH.sub.2 wherein Alk.sup.1 is as defined above; (1-8C)alkyl; lower alkyl monosubstituted with lower cycloalkyl, phenyl, 2-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, (3,4-methylenedioxy)-phenyl, 1-naphthyl, 2-naphthyl or Het wherein Het is as defined hereinabove; or R.sup.7 R.sup.8 NC(O)CH.sub.2 wherein PA1 (a) R.sup.7 is lower alkyl and R.sup.8 is lower alkyl or lower alkyl monosubstituted with phenyl or Het wherein Het is as defined hereinabove; or PA1 (b) R.sup.7 is lower alkyl and R.sup.8 is R.sup.9 R.sup.10 N--Alk.sup.2 wherein R.sup.9 and R.sup.10 each is lower alkyl and Alk.sup.2 is as defined hereinabove; or PA1 (c) R.sup.7 is lower alkyl and R.sup.8 is 2-morpholino-2-oxoethyl, 3-morpholino-3-oxopropyl or 3-(4-methyl-1-piperazinyl)-3-oxopropyl; or PA1 (d) R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, thiomorpholino or 4-(lower alkyl)-1-piperazinyl; PA1 R.sup.2 is lower alkyl, (lower cycloalkyl)methyl, 1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, (1-methyl-1H-imidazol-4-yl)methyl, 2-thienylmethyl, 2-oxazolylmethyl, 4-oxazolylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, (2-methyl-4-thiazolyl)methyl, (2-amino-4-thiazolyl)methyl, [2-(methylamino)-4-thiazol-yl]methyl, 2-pyridinylmethyl or 3-pyridinylmethyl; and PA1 B is as defined in the last instance; with the proviso that when A is the oxygen bearing radical (lower alkoxy)CR.sup.5A (R.sup.6A)CH.sub.2 wherein R.sup.5A and R.sup.6A are as defined hereinbefore, then R.sup.1 is R.sup.7 R.sup.8 NC(O)CH.sub.2 wherein R.sup.7 and R.sup.8 are as defined in the last instance; or PA1 a therapeutically acceptable acid addition salt thereof. PA1 (a) coupling a monoprotected dicarboxylic acid of formula 2 EQU W.sup.1 --C(O)CH.sub.2 CH(R.sup.2)R(O)OH 2 PA1 wherein W.sup.1 is a carboxy protecting group and R.sup.2 is as defined hereinbefore with an amine of formula H-B wherein B is as defined herein to obtain the corresponding protected amido acid of formula 3 EQU W.sup.1 --C(O)CH.sub.2 CH(R.sup.2 C(O)--B 3 PA1 wherein W.sup.1, R.sup.2 and B are as defined hereinbefore; PA1 (b) reacting the latter compound with a deprotecting agent to obtain the corresponding amido acid of formula 4 EQU HO--C(O)CH.sub.2 CH(R.sup.2)C(O)--B 4 PA1 wherein R.sup.2 and B are as defined hereinbefore; and PA1 (c) coupling the latter amido acid with an amine of formula ANH(R.sup.1) wherein A and R.sup.1 are as defined hereinbefore; and, if required, eliminating any protective groups from the instant product, to obtain the corresponding compound of formula 1. PA1 (d) coupling an amine of formula ANH(R.sup.1) in which A and R.sup.1 are as defined hereinbefore with a monoprotected dicarboxylic acid of formula 5 EQU HO--C(O)CH.sub.2 CH(R.sup.2)C(O)--W.sup.2 5 PA1 wherein R.sup.2 is as defined herein and W.sup.2 is a carboxy protective group to obtain the corresponding protected amido acid of formula 6 EQU A--N(R.sup.1)C(O)CH.sub.2 CH(R.sup.2)C(O)--W.sup.2 6 PA1 wherein A, R.sup.1 R.sup.2 and W.sup.2 are as defined hereinbefore; PA1 (e) reacting the latter compound with a deprotecting agent to obtain the corresponding amido acid of formula 7 EQU A--N(R.sup.1)C(O)CH.sub.2 CH(R.sup.2)C(O)--OH 7 PA1 wherein A, R.sup.1 and R.sup.2 are as defined hereinbefore; and PA1 (f) coupling the latter amido acid with an amine of formula H-B wherein B is as defined hereinbefore; and, if required, eliminating any protective groups from the instant product, to obtain the corresponding compound of formula 1.